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1.
Altern Ther Health Med ; 3(2): 40-7, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9061988

ABSTRACT

Many problems of health promotion or prevention call for an understanding of relations among variables embedded in complex causal webs that may include psychosocial, cultural, or environmental factors as well as biological dysfunction. Experimental investigation of these kinds of research problems is frequently impossible or not feasible. Causal modeling, particularly latent variable structural modeling, can provide a useful alternative to manipulative experimentation when one is trying to build and test explanatory models in a rigorous and systematic fashion. A hypothetical model of fibromyalgia is presented to illustrate how latent variable models can prove useful when the malady under investigation is of relatively complex multifactorial origin. Topics discussed include the fundamental notion underlying causal models, how such models solve problems due to measurement error, and why both cross-sectional and longitudinal models deserve consideration. A number of applications in medical research are described.


Subject(s)
Complementary Therapies , Female , Fibromyalgia , Health Promotion , Humans , Life Change Events , Male
2.
Blood ; 69(4): 1096-101, 1987 Apr.
Article in English | MEDLINE | ID: mdl-3493816

ABSTRACT

Purified preparations of normal C1(-)-inhibitor (C1(-)-INH) formed high mol wt complexes with plasma kallikrein that were stable during sodium dodecyl sulfate (SDS)-gel electrophoresis, but most of the dysfunctional C1(-)-INH proteins isolated from plasma of patients with type II hereditary angioneurotic edema (HANE) did not. Two of eight dysfunctional C1(-)-INH proteins were cleaved to lower mol wt forms that were not seen following the reaction of normal C1(-)-INH with equimolar amounts, or less, of plasma kallikrein. Only the higher mol wt component of normal C1(-)-INH (106,000 mol wt) appeared to form a stable complex with the plasma kallikrein, whereas both the 106,000 and 96,000 mol wt forms made stable complexes with C1-s. When a preparation of normal C1(-)-INH containing a homogeneous single band of C1(-)-INH was exposed to C1-s or kallikrein, a "doublet" form evolved in which the heaviest band was in the original position of native C1(-)-INH; C1-s cleavage provided a second band of 96,000; and cleavage by kallikrein, a second band of 94,000 mol wt. We conclude that dysfunctional C1(-)-INH proteins from plasma of persons with type II hereditary angioneurotic edema have impaired interactions with plasma kallikrein and are heterogeneous with respect to these interactions. Moreover, the requirements for the formation of stable complexes between normal C1(-)-INH and plasma kallikrein differed from those for stable complex formation with C1-s. The doublet form of C1(-)-INH, which purified preparations frequently demonstrate, may be due to prior cleavage by C1-s or kallikrein.


Subject(s)
Angioedema/blood , Complement Activating Enzymes/metabolism , Complement C1 Inactivator Proteins/metabolism , Complement C1/metabolism , Kallikreins/metabolism , Complement C1s , Electrophoresis, Polyacrylamide Gel , Humans , Molecular Weight , Protein Binding
3.
J Clin Invest ; 75(1): 124-32, 1985 Jan.
Article in English | MEDLINE | ID: mdl-3965500

ABSTRACT

C1(-)-inhibitor (C1(-)-INH) proteins from normal persons and members of eight different kindred with dysfunctional C1(-)-INH proteins associated with hereditary angioneurotic edema (HANE) were compared with respect to their inhibitory activity against purified preparations of C1s-, plasma kallikrein, activated forms of Hageman factor, and plasmin. Each dysfunctional C1(-)-INH protein showed a unique spectrum of inhibitory activity against these enzymes. Although none of the dysfunctional C1(-)-INH proteins significantly impaired amidolysis by plasmin, all but one inhibited activated Hageman factor. One purified dysfunctional C1(-)-INH (Ta) inhibited purified C1s- to a normal degree. Another C1(-)-INH (Za) had almost seven times as much inhibitory activity as normal C1(-)-INH against activated Hageman factor, but had decreased activity against C1s- and no activity against plasmin. Analyses of mixtures of plasmin and C1(-)-INH proteins in SDS gel electrophoresis revealed variability in the patterns of complex formation and cleavage of dysfunctional proteins after exposure to C1s- and plasmin. Some bound to plasmin and were cleaved, even though none significantly impaired the amidolytic activity of plasmin. Two were cleaved by C1s-, whereas neither normal or other dysfunctional C1(-)-INH were cleaved. Dysfunctional C1(-)-INH proteins from patients with HANE are thus heterogeneous in their inhibitory properties and there must be different structural requirements for the inhibition of the various plasma enzymes that can be regulated by normal C1(-)-INH. The data suggest that in addition to common sites of interactions between these proteases and C1(-)-INH, there are also points of contact that are specific for each protease. Genetic mutations leading to structural changes at some of these sites may have differing effects on the interaction between individual proteases and abnormal C1(-)-INH proteins. These alterations may allow these proteins to serve as probes for structural requirements for inhibitory actions of normal C1(-)-INH.


Subject(s)
Angioedema/genetics , Complement C1 Inactivator Proteins/physiology , Angioedema/immunology , Complement C1 Inactivator Proteins/metabolism , Electrophoresis, Polyacrylamide Gel , Humans , Sodium Dodecyl Sulfate
5.
Br J Pharmacol ; 72(1): 81-8, 1981 Jan.
Article in English | MEDLINE | ID: mdl-7225714

ABSTRACT

Anticoagulant activity of dermatan sulphates is unaffected by antiserum specific for antithrombin III (AT III) unless the glycosaminoglycan preparation contains demonstrable heparin. 2 Only dermatan sulphate preparations of considerable heparin content potentiate AT III inhibition of thrombin, factor Xa and plasmin. 3 These data suggest that dermatan sulphates exert anticoagulant activity which, unlike that of heparin, is largely or totally independent of AT III.


Subject(s)
Anticoagulants/pharmacology , Antithrombin III/physiology , Chondroitin/analogs & derivatives , Dermatan Sulfate/pharmacology , Animals , Cattle , Heparin/physiology , Immune Sera/pharmacology , Protease Inhibitors/pharmacology , Swine , Thrombin Time
7.
Br J Pharmacol ; 69(4): 675-7, 1980 Aug.
Article in English | MEDLINE | ID: mdl-6159941

ABSTRACT

1 Comparison of the effects of sulphated polysaccharides on thrombin-induced clotting of normal and antithrombin III-deficient plasmas suggests the involvement of antithrombin III (AT III) in the anticoagulant activities of cellulose, dextran and xylan sulphates. 2 AT III appears to play little or no role in the anticoagulant activity of carrageenans.


Subject(s)
Anticoagulants , Blood Coagulation/drug effects , Cellulose/pharmacology , Glycosaminoglycans/pharmacology , Antithrombin III Deficiency , Carrageenan/pharmacology , Dermatan Sulfate/pharmacology , Dextrans/pharmacology , Heparin/pharmacology , Humans , Thrombin Time , Xylans/pharmacology
11.
Br J Pharmacol ; 68(4): 645-9, 1980 Apr.
Article in English | MEDLINE | ID: mdl-7378640

ABSTRACT

1 Cellulose sulphate, like heparin, prolonged the clotting time in partial thromboplastin time (PTT) assays, inhibited the amidolytic activity of thrombin, was without effect on amidolysis catalysed by activated coagulation factor X(Xa), and potentiated the inhibition of both thrombin and Xa by antithrombin III (AT). 2 The anticoagulant activity of cellulose sulphate in PTT assays was, like that of heparin and heparin sulphate, but unlike that of dermatan sulphate, reduced by prior incubation of plasma with antiserum specific for AT. 3 These results, which suggest that the anticoagulant activity of cellulose sulphate is at least partially mediated through AT, are discussed in terms of the structural features of polysaccharides required for AT activation.


Subject(s)
Anticoagulants , Antithrombin III/physiology , Cellulose/pharmacology , Adolescent , Adult , Dermatan Sulfate/pharmacology , Heparin/pharmacology , Humans , In Vitro Techniques , Male , Partial Thromboplastin Time , Polysaccharides/pharmacology , Thrombin/physiology
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